Recently, two forms or genetic hyperrension in humans have been described, both of which display salt sensitivity. These genetic defects involve a) overproduction of aldosterone and b) an abnormal epithelial Na channel. The complete understanding of how and why these genetic abnormalities produce hypertension is just beginning. It is likely that animal models will assist in the unraveling of the genetic determinants of salt sensitive hypertension. The most widely studied animal model is the Dahl SS/Jr rat; its relative, the Dahl SR/Jr rat does not develop hypertension eating a high salt diet. We have obtained preliminary data indicating that the inner medullary collecting duct cells of prehypertensive Dahl S rats, when cultured on filters, absorb twice as much Na as inner medullary collecting duct cells cultured from Dahl R rats. Aldosterone stimulates Na transport by both the S and R monolayers, but the stimulation is greater in S monolayers. This observation is consistent with the idea that an (inappropriately) elevated rate of Na absorption by S kidneys plays a crucial role in the development of hypertension. The analysis of the ion transport systems of these cells indicates that the higher rate of Na transport by S monolayers is largely due to the greater rate of Na entry into the cell across the luminal (apical) membrane. The molecular pathway involved is a Na channel, probably the same as has been discovered to be defective in one of the genetic forms of human hypertension (Liddle~s Syndrome). This Na channel can be regulated by aidosterone and other adrenocortical steroids. The proposed work will examine the hypothesis that genetic differences between the Dahl S and R rats are responsible for the differences in Na channel function. Three specific aspects of this general hypothesis will be addressed. First, we will determine if any of the 3 genes encoding the subunits of the Na channel cosegregate with hypertension in F2 populations. Second, we will determine the extent to which the mRNA for the 3 subunits is regulated by adrenal steroids. At the same time we will determine to what extent steroid - hormone regulation of these subunits differs between the S and R strains. Third, we will study certain aspects of Na transport in a newly developed congenic rat strain. This strain has the 11 beta-hydroxylase gene from the R rat superimposed on the S rat genetic background. Using this model, we will be able to address important aspects of the mechanism whereby (genetically) abnormal steroid production contributes to enhanced Na transport and to the pathogenesis of hypertension. The results of these experiments will provide important information regarding the genetic mechanisms contributing to elevated rates of Na transport by the kidney and insights as to the mechanisms whereby these abnormalities contribute to hypertension.